We demonstrate outcomes of the prospective, multicenter, phase II study of PTCy n patients undergoing HLA-matched or HLA 1–2 allele mismatched PBSCT. As the primary endpoint, incidence of grade III-IV acute GVHD was only 2.3%, which was clearly below the pre-defined threshold. Our results demonstrated that PTCy effectively suppressed severe acute GVHD in patients who received HLA-matched or HLA 1–2 allele mismatched PBSCT.
In our study, the incidences of II-IV acute GVHD, III-IV acute GVHD, all grade chronic GVHD at 2 years, and moderate-severe chronic GVHD at 2 years were 16.3%, 2.3%, 14.0%, and 4.7%, respectively. Although our study included more patients receiving MAC and HLA-mismatch PBSCT, the incidence of acute and chronic GVHD was at least comparable to or lower than that of the BMT CTN 1703 trial, in which the incidences of II-IV acute GVHD, III-IV acute GVHD, and all grade chronic GVHD were 53.8%, 6.3%, and 21.9%, respectively [1], and the HOVON-96 trial, in which the incidences of II-IV acute GVHD, III-IV acute GVHD, all grade chronic GVHD, and extensive chronic GVHD were 30%, 6%, 43%, and 16%, respectively. [2]. Less incidence of GVHD may be associated with more homogenous Japanese population than Caucasian.
In our study, GRFS at 1-year was 69.8%. In the BMT CTN 1701 trial and HOVON-96 trial, the GRFS at 1 year were 52.7% and 45%, respectively [1, 2]. The slightly lower GRFS in the HOVON-96 study might be attributed to differences in immunosuppressive agents combined with PTCy: CSP alone was used in the HOVON-96 study [2, 18].
The optimal dose of PTCy is still controversial. The current standard PTCy dose is 50 mg/kg for 2 days for a total of 100 mg/kg [19, 20]. We have shown in previous studies that the dose of PTCy in HLA-haploidentical PBSCT could be reduced to 80 mg/kg [21]. A retrospective, cohort study conducted in Europe showed that a reduced dose of PTCy (80 mg/kg) in patients over 65 or 60 years of age with a history of cardiac events was associated with similar survival outcomes without increasing risk of GVHD [22]. Although data are limited on PTCy dose reduction in HLA-matched and HLA 1–2 allele mismatched transplantation, the incidence of GVHD in our study may be low enough to test dose reduction of PTCy in future.
The incidence of CRS in this study was lower than that of CRS in our previous studies of HLA-haploidentical PBSCT with PTCy [12, 13, 21]. In this study, the incidence of CRS tended to be lower in HLA-matched PBSCT compared to HLA 1–2 allele mismatched PBSCT, although the difference was not statistically significant. It is likely that degree of HLA mismatch is risk for CRS. Particularly, HLA-DR mismatch was a risk for CRS, as previously shown [23]. Although there was no significant difference in clinical outcome between patients with and without CRS in our study, a previous study suggested that HLA-class II mismatches decreased relapse [24]. Donor selection issue for PTCy transplant will be a focus of future research [25, 26].
The limitations of this study include a single-arm study design and too small number of patients to allow subgroup analysis, such as influences of conditioning intensity and the degree of HLA matching. Further studies are needed to addressthese issues.
In conclusion, we conducted a prospective, multicenter, phase II study of PTCy in patients undergoing HLA-matched or HLA 1–2 allele mismatched PBSCT. Our results indicate that PTCy is a valid option for GVHD prophylaxis in patients receiving HLA-matched or HLA 1–2 allele mismatched PBSCT.